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ROS Targets G Proteins

Reactive oxygen species (ROS), such as H2O2, can cause activation of tyrosine kinases, small guanosine triphosphatases, and the mitogen-activated protein kinase ERK (extracellular signal-regulated kinase). Nishida et al. propose that direct targets of ROS include alpha subunits of heterotrimeric guanine nucleotide-binding proteins (G proteins). In their experiments, overexpression of the COOH-terminus of the β-adrenergic receptor kinase in rat neonatal cardiomyocytes inhibited H2O2-induced activation of ERK, Akt (another kinase), and Src (a tyrosine kinase), presumably by sequestering G protein βγ subunits. In crude membrane preparations from neonatal myocytes, exposure to H2O2 increased the proportion of Gαo and Gαi in the active (trypsin-insensitive) conformation. Exposure of purified Go to H2O2 appeared to cause subunit dissociation and enhanced binding of guanosine 5'-O-(3'-triotriphosphate) (GTP-γ-S) in a manner not reversible by the antioxidant N-acetyl-L-cysteine. Separate exposure of α or βγ subunits revealed only the α subunits to be sensitive to H2O2. Activation of ERKs and Akt is associated with cell survival, and the authors suggest that signaling through G proteins could help cells adapt to oxidative stress.